1. Field of the Invention
The present invention relates to novel pharmaceutical compositions including magnesium compounds and to novel methods of treatment using the same, and is particularly directed to compositions for local application, such as topical, inhalational, rectal administration, including optionally systemic administration as a supplement thereto, and to novel treatments using the same.
2. The State of the Art
The magnesium cation is an essential mineral for many animals, including mammals, and especially for humans. As used herein, the term "magnesium" is intended to mean the salt or free ion form (as opposed to the non-ionic form). As such, magnesium is also a cofactor in numerous enzymatic reactions. It is involved in phosphate transfer from ADP and ATP muscle contractility, and neuronal transmission. The majority of magnesium in the human body is located in the bones in the form of phosphates and carbonates, and the remainder is found principally in the liver and muscles; red blood cells also contain magnesium. Magnesium inhibits nerve impulses and relaxes muscle contractions, thereby functioning antagonistically to calcium. On the other hand, like calcium, magnesium can bind phosphates and can substitute for calcium as a bone or tooth mineral. Accordingly, systemic (oral) calcium supplementation is often administered when magnesium is given systemically.
Various magnesium compounds have been used via intramuscular, oral, and intravenous routes of administration For example, magnesium acetate is used as a source of magnesium and as an acetate supply of bicarbonate in hemodialysis or peritoneal dialysis solutions; magnesium chloride is likewise used in dialysis solutions.
Magnesium gluconate has been used in the treatment of myocardial infarction. Magnesium gluconate has also been indicated for use as an adjunct in alleviating eclampsia, in the treatment of fetal distress, and in controlling premature/preterm labor where adrenergic receptor antagonists (e.g., ritodrine) are contra-indicated or poorly tolerated.
Magnesium sulfates commonly available in dry form as epsom salts, has been indicated in the form of a paste for use in the treatment of inflammatory skin conditions. However, prolonged or repeated use has been found to damage the skin. It has been postulated that magnesium sulfate paste may prevent bacterial growth by creating a strong osmotic gradients whereby the bacteria are killed effectively by dehydration; recent reports have suggested the same osmotic antibacterial effect when using salt or sugar (as reported for thoracic surgical wounds). Magnesium sulfate also has been indicated for internal use in treating bronchial asthma and cardiovascular disorders (eg., cardiac arrhythmia hypertension, and tachycardia)
Magnesium also has been taken internally and has been postulated to prevent dental caries, although experimental studies are equivocal. (H. Luoma, "The role of magnesium in the aetiology and prevention of caries: some new findings and implications," Magnesium Research, 1, 3/4, 223-230 (1988).)
Direct injection and oral administration of magnesium sulfate has been suggested for treating soft tissue calcification. (L. Steidl et al., "Soft tissue calcification treated with local and oral magnesium therapy," Magnes Res. (England), June 1990, 3(2), p. 113-9.)
Inhaled magnesium sulfate has been found to reduce the histamine bronchoprovocation test in asthmatics, and has been noted to be useful in decreasing bronchial hyper-reactivity (that is, in attenuating histamine-induced broncho-constriction). (G. Rolla et al., "Dose-Related Effect of Inhaled Magnesium Sulfate on Histamine Bronchial Challenge in Asthmatics," Drugs Exptl. Clin. Res., XIV(9) 609-612 (1988), and "Reduction of histamine-induced bronchoconstriction by magnesium in asthmatic subjects," Allergy, 42, 186-188 (1987).) The authors recommend that the aerosol solution be iso-osmolar and at near-physiological pH. Inhaled magnesium sulfate also has been investigated as an adjuvant in treating asthma. (H. Manzke et al., "Magnesium sulfate as adjuvant in beta-2-sympathomimetic inhalation therapy of bronchial asthma," Pneumologie (Ger.), October 1990, 44(10), p. 1190-2.)
The topical use of magnesium salts has been suggested for the treatment of burns caused by hydrofluoric acid.
The topical use of magnesium chloride has been suggested as an alternative to commonly used corticosteroids for treating common skin diseases. (P. W. M. Copeman, "New non-steroid non-antibiotic skin medicaments," Brit. Med. J., Nov. 1, 1979, p. 264.) The authors disclose a cream or lotion including magnesium chloride in an amount of about 1.5%, and appear to be particularly concerned with inhibiting infection by gram-negative bacteria. Likewise, and as noted above, the use of magnesium sulfate paste and sugar have been suggested for inhibiting bacterial growth by creating a strong osmotic gradient. (P. Lowthian et al., "Sterculia for Wound Healing" (letter), The Lancet, Sep. 23, 1985, p.1186.)
Using a combination of magnesium and aluminum hydroxide has been suggested to inhibit localized dermal reactions to transdermal clonidine. The investigators found this combination less effective than hydrocortisone in alleviating the local dermatitis. (M. K. Ito et al., "Skin pretreatment and the use of transdermal clonidine," Am. J. Med, Jul. 18, 1981, 91(1A), p. 42S-49S.)
In general, when magnesium salts have been considered useful for pharmacotherapy, such salts have been used in solution having a maximum concentration that is isotonic. It is conventional pharmacological protocol to make solutions that are concentrated, at most, at the isotonic level, and more conventionally such solutions have a concentration that is hypotonic; hypertonic solutions are avoided because of their dehydrating and irritating effects.